RESUMO
We found a shared immunosuppressive microenvironment between foetal liver and hepatocellular carcinoma (HCC) which includes the re-emergence of foetal-associated endothelial cells (PLVAP/VEGFR2) and foetal-like (FOLR2) tumour-associated macrophages in HCC, mediated via VEGF-NOTCH signalling. The discoveries suggest possible novel targets for therapeutic interventions in HCC.
Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Evasão Tumoral , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Reprogramação Celular/genética , Reprogramação Celular/imunologia , Desenvolvimento Fetal/genética , Desenvolvimento Fetal/imunologia , Receptor 2 de Folato/fisiologia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Macrófagos/patologia , Macrófagos/fisiologia , Proteínas de Membrana/genética , Proteínas de Membrana/fisiologia , Camundongos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Evasão Tumoral/genética , Evasão Tumoral/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/fisiologia , alfa-Fetoproteínas/genética , alfa-Fetoproteínas/fisiologiaRESUMO
Idiopathic pulmonary fibrosis (IPF) is a chronic, fatal disease with high mortality and poor prognosis. It is characterized by a gradual decline in lung function, and there are currently no effective therapeutic methods. Folate is a water-soluble B vitamin that plays an important role in one-carbon transfer reactions, nucleic acid biosynthesis and methylation reactions. Studies have shown that folate may participate in the pathogenesis of IPF through ways of DNA repair, methylation, and reactive oxygen species. Macrophage activation is an important early cellular event in IPF and the inflammatory response that they trigger is a significant feature of IPF. Folate receptor-ß (FR-ß) is a cell surface glycosylphosphatidylinositol-anchored glycoprotein that can mediate the unidirectional transport of folate into cells. And it has been found in previous studies that FR-ß is usually overexpressed on activated macrophages, but the expression on resting macrophages was undetectable. Therefore, targeting FR-ß may have potential value for the early diagnosis and therapy of IPF. Our goal is to highlight the biological role of folate and FR-ß in IPF, and we hope to provide helpful insight for clinical treatment strategies.
Assuntos
Receptor 2 de Folato/fisiologia , Ácido Fólico/fisiologia , Fibrose Pulmonar Idiopática/etiologia , Macrófagos/fisiologia , Polaridade Celular , Receptor 2 de Folato/antagonistas & inibidores , Receptor 2 de Folato/química , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Receptor 4 Toll-Like/fisiologiaRESUMO
Folate, also known as vitamin B9, is necessary for essential cellular functions such as DNA synthesis, repair, and methylation. It is supplied to the cell via several transporters and receptors, including folate receptor (FR) ß, a GPI-anchored protein belonging to the folate receptor family. As FRß shows a restricted expression to cells of myeloid origin and only a subset of activated macrophages and placental cells have been shown to express functional FRß, it represents a promising target for future therapeutic strategies. In this study, we performed affinity purification and mass spectrometric analysis of the protein microenvironment of FRß in the plasma membrane of human FRß(+) macrophages and FRß-transduced monocytic THP-1 cells. In this manner, we identified a novel role of FRß: that is, we report functional interactions of FRß with receptors mediating cellular adhesion, in particular the CD11b/CD18 ß2 integrin heterodimer complement receptor type 3/Mac-1. This interaction results in impeded adhesion of FRß(+) human primary macrophages and THP-1 cells to collagen in comparison with their FRß(-) counterparts. We further show that FRß is only expressed by human macrophages when differentiated with M-CSF. These findings thus identify FRß as a novel CD11b/CD18 regulator for trafficking and homing of a subset of macrophages on collagen.
Assuntos
Antígeno CD11b/fisiologia , Antígenos CD18/fisiologia , Colágeno/farmacologia , Receptor 2 de Folato/fisiologia , Macrófagos/fisiologia , Adesão Celular , Movimento Celular , Proliferação de Células , Células Cultivadas , Ácido Fólico/metabolismo , Humanos , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
Structure-activity relationships for cellular uptake and inhibition of cell proliferation were studied for 2-amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolates in which the terminal l-glutamate of the parent structure (7) was replaced by natural or unnatural amino acids. Compounds 7 and 10-13 were selectively inhibitory toward folate receptor (FR) α-expressing Chinese hamster ovary (CHO) cells. Antiproliferative effects of compounds 7 and 9-13 toward FRα- and FRß-expressing CHO cells were only partly reflected in binding affinities to FRα and FRß or in the docking scores with molecular models of FRα and FRß. Compounds 7 and 11 were potent inhibitors of glycinamide ribonucleotide formyltransferase in de novo purine biosynthesis in KB human tumor cells. These studies establish for the first time the importance of the α- and γ-carboxylic acid groups, the length of the amino acid, and the conformation of the side chain for transporter binding and biological activity of 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolates.